PNH pathophysiology

PNH pathophysiology

Paroxysmal nocturnal haemoglobinuria (PNH) is a bone marrow disease caused by the clonal expansion of one or more haematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol glycan class A gene (PIG-A).1 This X-chromosome gene regulates the first step in the synthesis of glycosylphosphatidylinositol (GPI) anchors, which are essential for tethering a number of complement-regulating surface proteins to the cell membrane of erythrocytes, leucocytes and platelets.

Two GPI-linked proteins play a particularly important role:

CD55 (DAF, decay-accelerating factor) controls the first steps of the complement cascade by regulating the activity of the enzymes C3 and C5 convertases.1-4

CD59 (MIRL, membrane inhibitor of reactive lysis) inhibits the formation of the terminal complement complex by preventing the incorporation of C9 in the C5b-8 complex, thereby preventing the formation of membrane attack complex (MAC or C5b-9).1-4

Blood cells that are partially or completely deficient in these protective factors (CD55 and CD59) have an increased susceptibility to the lytic effects of activated complement.1-3 When the C5b-9 complex binds to the deficient erythrocyte cell surface, plasma membrane ion permeability is increased and this can result in cell death through lysis.5,6

PNH involves the increased sensitivity of blood cells to the lytic action of complement due to the partial or complete lack of CD55 and CD59 proteins

Clonal populations of varying significance

Clonal populations of varying significance

More than 100 mutations of the PIG-A gene (mainly small insertions or deletions) have been identified.4 These mutations occur at high frequency (2–4 cells per 100,000) in healthy individuals and appear to be polyclonal.4,8

In patients with PNH, two types of haematopoietic stem-cell clone can be identified: those that give rise to cells with partial GPI deficiency (Type II) and those that give rise to cells with complete GPI deficiency (Type III) during the cellular maturation process. Cells with normal GPI levels are known as Type I.4

Different types of clonal populations

All three types of cells may be found in a patient at the same time.4 Type III erythrocytes (completely GPI deficient) are 15–25 times more sensitive than normal cells to the lytic effects of activated complement and, thus, have a half-life of only 6 days (compared to 60 days for normal, Type I erythrocytes). Type II cells (partially GPI deficient) are 3–5 times more sensitive than normal erythrocytes.3

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PNH involves an acquired somatic mutation of the PIG-A gene, causing a partial or complete deficiency in GPI anchors